A key challenge in the genomic era is to understand how alleles and allelic combinations influence variability in biological pathways and the onset of common, complex disease. Variation in intricate biological pathways plays an important role in human health. The development of methodology to systematically evaluate the genetic variability within an entire biological pathway and reveal how alleles and allelic combinations affect the development of traits and disease would be an important advance. To this end, we propose to comprehensively characterize the genetic variation of 44 genes central to the sex steroid pathway and evaluate if alleles from these genes, either alone or in combination, can predict the variability in serum levels of estrogen and testosterone in a large population based cohort. The relevance of variation in sex steroid pathway genes to disease will first be examined using the sex steroid influenced disease Systemic Lupus Erythematosus.